This proposal describes a five-year career development program to prepare the Candidate, Dr. Ioannis Karakikes, for a career as an independent investigator. This program will build on Dr. Karakikes' background as a basic cell and molecular biologist by providing expertise in molecular cardiology and multimodality cardiac imaging methodologies. The mentor is Dr. Roger Hajjar who is Professor of Medicine and Director of the Cardiovascular Research Center at the Mount Sinai School of Medicine. The proposed mentor is an expert in cardiac physiology and cardiac gene therapy. The K99 phase will consist of structured mentorship by the primary mentor, complementary meetings with an advisory committee, formal coursework, a provocative research project and a program of career transition. In his preliminary studies, Dr. Karakikes has developed and validated a set of molecular and cell biology tools to study the potential role of microRNAs (miRNAs) in the pathogenesis of diabetic cardiomyopathy. Dr. Karakikes has identified several diabetic cardiomyopathy- associated miRNAs, however, the proposed studies will focus on the detailed characterization of miRNA-152 (miR-152). In preliminary studies, Dr. Karakikes has demonstrated that miR-152 overexpression profoundly altered glucose uptake and induced a hypertrophic response and contractile dysfunction in primary cardiomyocytes in vitro. In the research approach, Dr. Karakikes will build on these findings to test the hypothesis that miR-152 regulates cardiac contractility and ventricular remodeling in vivo. To date the Candidate has accrued the technical competencies necessary to conduct the proposed comprehensive analysis of miRNA modulated cardiac function. To address the overall goal of the project, an inducible cardiac- specific miR-152 transgenic mouse model was generated. This model will be used to phenotypically characterize the role of miRNA in cardiac function, ventricular remodeling and to determine its target genes. In Specific Aims 1 and 2 of the K99 phase, the Candidate will assess cardiac function in miR-152 overexpressing mice using multiparametric imaging, hemodynamic and electrophysiological methodologies. These studies will be coupled with detailed histological and molecular analysis of cardiac tissue samples. During Specific Aims 3 and 4 of the R00 segment, the Candidate will use a comprehensive set of molecular approaches to identify the specific target genes for miR-152 and possible regulatory networks that mediate pathological remodeling in the diabetic heart. Dr Karakikes' ultimate goal is to use this information to develop novel therapeutic modalities for diabetes-related cardiac dysfunction. Collectively, the proposed work will elucidate novel mi-RNA-based mechanisms underlying cardiovascular function and pathophysiology. In addition, this work will provide a foundation for future studies on the role of miR-152 and other miRNAs in heart function to be eventually carried out by Dr. Karakikes as an independent investigator.